Department of Pathology, Tianjin Medical University, Tianjin, China.
Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.
J Cell Mol Med. 2018 Jul;22(7):3475-3488. doi: 10.1111/jcmm.13625. Epub 2018 Apr 14.
Tumour protein p53-inducible nuclear protein 1 (TP53INP1) is a tumour suppressor associated with malignant tumour metastasis. Vasculogenic mimicry (VM) is a new tumour vascular supply pattern that significantly influences tumour metastasis and contributes to a poor prognosis. However, the molecular mechanism of the relationship between TP53INP1 and breast cancer VM formation is unknown. Here, we explored the underlying mechanism by which TP53INP1 regulates VM formation in vitro and in vivo. High TP53INP1 expression was not only negatively correlated with a poor prognosis but also had a negative relationship with VE-cadherin, HIF-1α and Snail expression. TP53INP1 overexpression inhibited breast cancer invasion, migration, epithelial-mesenchymal transition (EMT) and VM formation; conversely, TP53INP1 down-regulation promoted these processes in vitro by functional experiments and Western blot analysis. We established a hypoxia model induced by CoCl and assessed the effects of TP53INP1 on hypoxia-induced EMT and VM formation. In addition, we confirmed that a reactive oxygen species (ROS)-mediated signalling pathway participated in TP53INP1-mediated VM formation. Together, our results show that TP53INP1 inhibits hypoxia-induced EMT and VM formation via the ROS/GSK-3β/Snail pathway in breast cancer, which offers new insights into breast cancer clinical therapy.
肿瘤蛋白 p53 诱导核蛋白 1（TP53INP1）是一种与恶性肿瘤转移相关的肿瘤抑制因子。血管生成拟态（VM）是一种新的肿瘤血管供应模式，它显著影响肿瘤转移，并导致预后不良。然而，TP53INP1 与乳腺癌 VM 形成之间关系的分子机制尚不清楚。在这里，我们探讨了 TP53INP1 在体外和体内调节 VM 形成的潜在机制。高表达的 TP53INP1 不仅与不良预后呈负相关，而且与 VE-钙黏蛋白、HIF-1α 和 Snail 的表达呈负相关。TP53INP1 的过表达抑制乳腺癌的侵袭、迁移、上皮-间充质转化（EMT）和 VM 形成；相反，通过功能实验和 Western blot 分析，TP53INP1 的下调促进了这些过程。我们建立了 CoCl 诱导的缺氧模型，并评估了 TP53INP1 对缺氧诱导的 EMT 和 VM 形成的影响。此外，我们证实了活性氧（ROS）介导的信号通路参与了 TP53INP1 介导的 VM 形成。总之，我们的结果表明，TP53INP1 通过 ROS/GSK-3β/Snail 通路抑制乳腺癌缺氧诱导的 EMT 和 VM 形成，为乳腺癌的临床治疗提供了新的见解。
